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Mitochondrial complex 2 deficiency, nuclear type 2(MC2DN2)

MedGen UID:
1742371
Concept ID:
C5436933
Disease or Syndrome
Synonym: MITOCHONDRIAL COMPLEX II DEFICIENCY, NUCLEAR TYPE 2
 
Gene (location): SDHAF1 (19q13.12)
 
Monarch Initiative: MONDO:0030935
OMIM®: 619166

Definition

Mitochondrial complex II deficiency nuclear type 2 (MC2DN2) is an autosomal recessive multisystemic metabolic disorder with variable severity and features. Most patients present with neurologic deterioration in infancy or early childhood after normal early development. Features include loss of motor skills, spastic paresis, dystonia, and loss of speech associated with increased serum and CSF lactate. Some patients may have mental decline or visual loss. Skeletal muscle samples show isolated complex II deficiency, and proton MRS shows increased succinate levels in the CSF and brain white matter. Brain imaging usually shows progressive leukoencephalopathy. Although the pattern of brain involvement may not be characteristic of Leigh syndrome (see 256000), postmortem examination in 1 patient showed multifocal spongiform encephalomyelopathy consistent with a diagnosis of Leigh syndrome. The most severely affected patients die of multiorgan failure and lactic acidosis, whereas others who survive may stabilize and regain some skills. Treatment with riboflavin may offer clinical improvement (summary by Brockmann et al., 2002 and Bugiani et al., 2006). For a discussion of genetic heterogeneity of MC2DN, see MC2DN1 (252011). [from OMIM]

Clinical features

From HPO
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Reduced brain N-acetyl aspartate level by MRS
MedGen UID:
868367
Concept ID:
C4022761
Finding
A decrease in the level of N-acetyl aspartate in the brain identified by magnetic resonance spectroscopy (MRS).

Recent clinical studies

Etiology

Gurubaran IS
Acta Ophthalmol 2024 Mar;102 Suppl 282:3-53. doi: 10.1111/aos.16661. PMID: 38467968
Hipps D, Dobson PF, Warren C, McDonald D, Fuller A, Filby A, Bulmer D, Laude A, Russell O, Deehan DJ, Turnbull DM, Lawless C
Bone 2022 May;158:116371. Epub 2022 Feb 19 doi: 10.1016/j.bone.2022.116371. PMID: 35192969
de Oliveira Ribeiro H, Cortez AP, de Ávila RI, da Silva ACG, de Carvalho FS, Menegatti R, Lião LM, Valadares MC
Fundam Clin Pharmacol 2020 Aug;34(4):444-457. Epub 2020 Mar 14 doi: 10.1111/fcp.12540. PMID: 32011031
Powell CA, Kopajtich R, D'Souza AR, Rorbach J, Kremer LS, Husain RA, Dallabona C, Donnini C, Alston CL, Griffin H, Pyle A, Chinnery PF, Strom TM, Meitinger T, Rodenburg RJ, Schottmann G, Schuelke M, Romain N, Haller RG, Ferrero I, Haack TB, Taylor RW, Prokisch H, Minczuk M
Am J Hum Genet 2015 Aug 6;97(2):319-28. Epub 2015 Jul 16 doi: 10.1016/j.ajhg.2015.06.011. PMID: 26189817Free PMC Article
Salminen A, Kaarniranta K, Kauppinen A, Ojala J, Haapasalo A, Soininen H, Hiltunen M
Prog Neurobiol 2013 Jul-Aug;106-107:33-54. Epub 2013 Jul 1 doi: 10.1016/j.pneurobio.2013.06.002. PMID: 23827971

Diagnosis

Mackay L, Gijavanekar C, Streff H, Price JF, Elsea SH, Scaglia F
Am J Med Genet A 2023 May;191(5):1366-1372. Epub 2023 Feb 7 doi: 10.1002/ajmg.a.63131. PMID: 36751706
Garone C, D'Souza AR, Dallabona C, Lodi T, Rebelo-Guiomar P, Rorbach J, Donati MA, Procopio E, Montomoli M, Guerrini R, Zeviani M, Calvo SE, Mootha VK, DiMauro S, Ferrero I, Minczuk M
Hum Mol Genet 2017 Nov 1;26(21):4257-4266. doi: 10.1093/hmg/ddx314. PMID: 28973171Free PMC Article
Kumar A, Corey C, Scott I, Shiva S, D'Cunha J
PLoS One 2016;11(8):e0160783. Epub 2016 Aug 8 doi: 10.1371/journal.pone.0160783. PMID: 27501149Free PMC Article
Abdulhag UN, Soiferman D, Schueler-Furman O, Miller C, Shaag A, Elpeleg O, Edvardson S, Saada A
Eur J Hum Genet 2015 Feb;23(2):159-64. Epub 2014 Apr 30 doi: 10.1038/ejhg.2014.85. PMID: 24781756Free PMC Article
Wollheim CB
Diabetologia 2000 Mar;43(3):265-77. doi: 10.1007/s001250050044. PMID: 10768087

Therapy

Carraway MS, Suliman HB, Jones WS, Chen CW, Babiker A, Piantadosi CA
Circ Res 2010 Jun 11;106(11):1722-30. Epub 2010 Apr 15 doi: 10.1161/CIRCRESAHA.109.214353. PMID: 20395592Free PMC Article
Yamada T, Goto M, Punj V, Zaborina O, Chen ML, Kimbara K, Majumdar D, Cunningham E, Das Gupta TK, Chakrabarty AM
Proc Natl Acad Sci U S A 2002 Oct 29;99(22):14098-103. Epub 2002 Oct 22 doi: 10.1073/pnas.222539699. PMID: 12393814Free PMC Article

Prognosis

Baechler SA, Factor VM, Dalla Rosa I, Ravji A, Becker D, Khiati S, Miller Jenkins LM, Lang M, Sourbier C, Michaels SA, Neckers LM, Zhang HL, Spinazzola A, Huang SN, Marquardt JU, Pommier Y
Nat Commun 2019 Jan 8;10(1):83. doi: 10.1038/s41467-018-07922-3. PMID: 30622257Free PMC Article
Aldera AP, Govender D
J Clin Pathol 2018 Feb;71(2):95-97. Epub 2017 Oct 25 doi: 10.1136/jclinpath-2017-204677. PMID: 29070651
Abdulhag UN, Soiferman D, Schueler-Furman O, Miller C, Shaag A, Elpeleg O, Edvardson S, Saada A
Eur J Hum Genet 2015 Feb;23(2):159-64. Epub 2014 Apr 30 doi: 10.1038/ejhg.2014.85. PMID: 24781756Free PMC Article
Willems PH, Valsecchi F, Distelmaier F, Verkaart S, Visch HJ, Smeitink JA, Koopman WJ
Cell Calcium 2008 Jul;44(1):123-33. Epub 2008 Mar 4 doi: 10.1016/j.ceca.2008.01.002. PMID: 18295330
Houstek J, Klement P, Floryk D, Antonická H, Hermanská J, Kalous M, Hansíková H, Hout'ková H, Chowdhury SK, Rosipal T, Kmoch S, Stratilová L, Zeman J
Hum Mol Genet 1999 Oct;8(11):1967-74. doi: 10.1093/hmg/8.11.1967. PMID: 10484764

Clinical prediction guides

Gurubaran IS
Acta Ophthalmol 2024 Mar;102 Suppl 282:3-53. doi: 10.1111/aos.16661. PMID: 38467968
Kotschi S, Jung A, Willemsen N, Ofoghi A, Proneth B, Conrad M, Bartelt A
Mol Metab 2022 Mar;57:101436. Epub 2022 Jan 6 doi: 10.1016/j.molmet.2022.101436. PMID: 34999280Free PMC Article
Ale-Agha N, Jakobs P, Goy C, Zurek M, Rosen J, Dyballa-Rukes N, Metzger S, Greulich J, von Ameln F, Eckermann O, Unfried K, Brack F, Grandoch M, Thielmann M, Kamler M, Gedik N, Kleinbongard P, Heinen A, Heusch G, Gödecke A, Altschmied J, Haendeler J
Circulation 2021 Dec 7;144(23):1876-1890. Epub 2021 Oct 21 doi: 10.1161/CIRCULATIONAHA.120.051923. PMID: 34672678
Abdulhag UN, Soiferman D, Schueler-Furman O, Miller C, Shaag A, Elpeleg O, Edvardson S, Saada A
Eur J Hum Genet 2015 Feb;23(2):159-64. Epub 2014 Apr 30 doi: 10.1038/ejhg.2014.85. PMID: 24781756Free PMC Article
Voets AM, Huigsloot M, Lindsey PJ, Leenders AM, Koopman WJ, Willems PH, Rodenburg RJ, Smeitink JA, Smeets HJ
Biochim Biophys Acta 2012 Jul;1822(7):1161-8. Epub 2011 Oct 17 doi: 10.1016/j.bbadis.2011.10.009. PMID: 22033105

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